Canine Transforming Growth Factor-β Receptor 2-Ig: A Potential Candidate Biologic for Melanoma Treatment That Reverses Transforming Growth Factor-β1 Immunosuppression

Cancer cells can evade host immune systems via multiple mechanisms. Transforming growth factor beta 1 (TGF-beta 1) is an immunosuppressive cytokine that induces regulatory T cell (Tregs) differentiation and is involved in immune evasion mechanisms in cancer. The inhibition of the TGF-beta 1 signaling pathway can suppress cancer progression and metastasis through the modulation of anticancer immune responses. However, to best of our knowledge, no implementation of treatments targeting TGF-beta 1 has been reported in dog cancers. This study aimed to examine whether TGF-beta 1 is upregulated in canine cancers. We measured TGF-beta 1 concentrations in culture supernatants of canine melanoma cell lines and in serum samples from dogs with oral malignant melanoma. TGF-beta 1 production was observed in several cell lines, and serum TGF-beta 1 levels were elevated in dogs with oral malignant melanoma. Interestingly, the addition of recombinant TGF-beta 1 to canine peripheral blood mononuclear cell cultures decreased Th1 cytokine production and increased differentiation of CD4(+)CD25(+)Foxp3(+) lymphocytes, suggesting that TGF-beta 1 is immunosuppressive in canine immune systems. We developed a decoy receptor for TGF-beta, namely TGF-beta RII-Ig, by identifying an open reading frame of the canine TGFBR2 gene. TGF-beta RII-Ig was prepared as a recombinant fusion protein of the extracellular region of canine TGF-beta RII and the Fc region of canine IgG-B. As expected, TGF-beta RII-Ig bound to TGF-beta 1. In the presence of TGF-beta 1, the treatment with TGF-beta RII-Ig increased Th1 cytokine production and decreased the differentiation of CD4(+)CD25(+)Foxp3(+) lymphocytes. Our results suggest that TGF-beta RII-Ig competitively inhibits the immunosuppressive effects of TGF-beta 1 and thereby activates immune responses. This study demonstrated the potential of TGF-beta RII-Ig as a novel biologic for canine melanoma.

Automated summary

The study found that TGF-beta 1 is upregulated in canine cancers, and TGF-beta RII-Ig can competitively inhibit the immunosuppressive effects of TGF-beta 1, thereby activating immune responses and potentially serving as a novel biologic for treating canine melanoma.